Solid-forming local anesthetic formulations for pain control

ABSTRACT

Solid-forming local anesthetic formulations for pain control can include a lidocaine base and tetracaine base, polyvinyl alcohol, water, and an emulsifier. The formulation can be prepared to be in a semi-solid state prior to application to a skin surface, can form a soft solidified layer after application, and can provide pain relief when applied to a skin surface proximate a pain site.

The present application is a continuation of U.S. patent applicationSer. No. 13/006,780, filed on Jan. 14, 2011, which claims the benefit ofU.S. Provisional Patent Application No. 61/294,927, filed Jan. 14, 2010.

BACKGROUND

Non-invasive pain control methods are desirable in treating pain, suchas neuropathic pain. It would be useful to provide formulations that areeasy to use, have good storage stability, particularly freeze-thawstorage stability, and are effective for non-invasive pain controltreatment.

DETAILED DESCRIPTION

Before particular embodiments of the present invention are disclosed anddescribed, it is to be understood that this disclosure is not limited tothe particular process and materials disclosed herein as such may varyto some degree. It is also to be understood that the terminology usedherein is used for the purpose of describing particular embodiments onlyand is not intended to be limiting, as the scope of the presentinvention will be defined only by the appended claims and equivalentsthereof.

In describing and claiming the present invention, the followingterminology will be used.

“Skin” is defined to include human skin (intact, diseased, ulcerous, orbroken), and mucosal surfaces that are usually at least partiallyexposed to air such as lips, genital and anal mucosa, and nasal and oralmucosa.

The term “solid-forming local anesthetic formulation” or “solid-formingformulation” refers to a formulation that is in the state of asemi-solid and comprises a local anesthetic, water, and a polymer beforebeing applied onto a skin surface. After being applied to a skin surfaceas a thin layer (e.g., 1 mm thick), the solid-forming local anestheticformulation forms a layer of a coherent solid after sufficientconcentration of water is evaporated from the formulation layer.Examples of semi-solid forms include creams, ointments, pastes, viscouslotions, gels, and the like. It is notable that the solid-formingformulations of the present disclosure are free of backing layers orbacking films and are formulated to be applied directly to a skinsurface as a semi-solid state without the need of a separate supportsubstrate (e.g. backing layer or backing firm) both before applicationand after being applied. The ability of the formulation to be applieddirectly to the skin without a backing layer, backing film, or othersupport substrate enhances the ability of the formulation to betteradhere to regions of a subjects skin that do not readily lend themselvesto traditional transdermal patches (i.e. those that include backinglayers or backing films). By enhancing adherence to such surfaces, thesolid-forming formulations are more effective in deliveringtherapeutically effective amounts of the local anesthetics, therebyproviding enhanced relief of the neuropathic pain.

As used herein, the term “semi-solid” refers to a composition having aviscosity of about 40,000 centipoise to about 800,000 centipoise. Asdiscussed above, compositions having viscosities in this range that canbe deemed semi-solids can include creams, ointments, pastes, viscouslotions, gels, and the like. It is notable that not all of the foregoingcompositions are considered to be semi-solids, but rather only thosethat having viscosities that fall within the above range. In one aspectof the disclosure, the semi-solid formulations can have a viscosity ofabout 70,000 centipoise to about 500,000 centipoise.

The phrases “sufficient amount of water” or “sufficient concentration ofwater” refers to an amount or a concentration of water evaporated froman applied layer of the formulation such that the formulationtransitions from a semi-solid to a coherent solid.

“Coherent solid” or “coherent soft solid” describes the solidified layerof the solid-forming local anesthetic formulation after a sufficientconcentration of water has evaporated (sufficient to cause thesolidification). The coherent soft solid remains adhered to the skin andis capable of maintaining good contact with the subject's skin forsubstantially the entire duration of desired application. Additionally,a “coherent solid” can have cohesive strength sufficient such that thesolid remains intact when peeled from the skin. In other words, cohesivesoft solids do not include dried lotions and other viscous semi-solidsthat are non-cohesive even after drying but rather, includescompositions that remain at least partially cohesive in the solid state,even after being removed from a skin surface. In one embodiment, thecoherent solid can be peelable from the skin, e.g., the coherent solidcan remain as a single large piece when peeled from the skin, or tearsinto 2 or 3 large pieces.

The term “initial state” when used to describe a solid-forming localanesthetic formulation refers to the state of the formulation beforebeing applied to a skin surface. The state of application in the initialstate is typically a semi-solid state, e.g., cream, gel, ointment,liquid, etc., and not the coherent solid state, e.g., peelable orotherwise removable solid that coherent as a thin solid layer.

The term “initial viscosity” refers to the viscosity of the formulationat room temperature (typically about 25° C.) prior to a freeze/thawcycle.

The term “freeze/thaw cycle” refers to the placement of the formulationin an environment having a temperature of −18° C. to −22° C. for aperiod of time of 48 hours followed by the thawing of the formulation ata temperature of about 25° C. for a period of 48 hours. One freezing andone thawing period together are considered to be one (1) freeze/thawcycle. It is noted that the temperature range reflects temperaturefluctuation associated with the typical cycling of a freezer set tofreeze at about −20° C.

The term “neuropathic pain” refers to any and all types of neuropathicpain regardless of the cause. Examples of specific sources ofneuropathic pain for which the methods of the present disclosure can beused include diabetic neuropathies and virus-caused neuropathies. Thetreatment of neuropathic pain as described herein refers to thealleviation or elimination of the neuropathic pain associated with aneuropathy.

The term “proximate” when referring to a location on a skin surface,particularly as it relates to the location of neuropathic pain, means anarea of skin directly over (in part or fully covering) or immediatelyadjacent to tissue from which the neuropathic pain is present.

The phrases “relief of neuropathic pain,” “relief of pain,” and“clinically relevant reduction of neuropathic pain”, and the like, areused interchangeably and are defined as an average reduction of 3 pointsor more from the baseline on an 11-point numeric pain rating scalecompared with placebo when tested using at least 12 subjects.

As used herein, a plurality of drugs, compounds, and/or solvents may bepresented in a common list for convenience. However, these lists shouldbe construed as though each member of the list is individuallyidentified as a separate and unique member. Thus, no individual memberof such list should be construed as a de facto equivalent of any othermember of the same list solely based on their presentation in a commongroup without indications to the contrary.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 0.01 to 2.0” should beinterpreted to include not only the explicitly recited values of about0.01 to about 2.0, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. Furthermore, such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described. Additionally, it is noted that allpercentages are in weight, unless specified otherwise.

With this background in mind, a formulation for pain control isprovided. In one embodiment, the formulation includes lidocaine andtetracaine, each in their base form. The formulation also includespolyvinyl alcohol, water, and an emulsifying agent having an HLB valueof less than 6.7. The formulation can have a water to polyvinyl alcoholweight ratio greater than 2.4.

In another embodiment, a formulation for treating neuropathic pain isprovided. The formulation includes lidocaine and tetracaine, each intheir base form, as well as polyvinyl alcohol, water, petrolatum, and anemulsifying agent. The emulsifying agent has an HBL value of less than5.

In yet another embodiment, a formulation for providing pain control cancomprise lidocaine and tetracaine in their base forms, polyvinylalcohol, and water. The formulation can have an initial viscosity ofabout 40,000 centipoise to about 800,000 centipoise, and can have anincrease in viscosity after 3 freeze/thaw cycles of less than 8 timesthe initial viscosity with a maximum viscosity of 1,500,000 centipoise.Each of the 3 freeze/thaw cycles can be determined by placement of theformulation in an environment of −18° C. to −22° C. for a period of timeof 48 hours followed by the thawing of the formulation at roomtemperature (about 25° C.) for a period of 48 hours.

In still another embodiment, a formulation for providing pain controlcan comprise from 4 wt % to 30 wt % of a eutectic mixture of lidocaineand tetracaine, from 10 wt % to 18 wt % polyvinyl alcohol, from 30 wt %to 50 wt % water, from 2 wt % to 13 wt % petrolatum, and from 2 wt % to6 wt % sorbitan monostearate. The water to polyvinyl alcohol weightratio can be greater than 2.4. Also, the formulation cab have an initialviscosity of about 70,000 centipoise to about 500,000 centipoise, andcan have an increase in viscosity after 3 freeze/thaw cycles of lessthan 8 times the initial viscosity with a maximum viscosity of 1,500,000centipoise. Each of the 3 freeze/thaw cycles can be determined byplacement of the formulation in an environment of −18° C. to −22° C. fora period of time of 48 hours followed by the thawing of the formulationat room temperature (about 25° C.) for a period of 48 hours.

Regarding the local anesthetic active ingredients described herein, thepresent disclosure is drawn primarily to mixtures of lidocaine andtetracaine, typically as a eutectic mixture where each local anestheticis in its base form. Typically, the mixture of the local anestheticswill be present in total within the composition as a whole at from 4 wt% to 30 wt %, and more typically from 8 wt % to 20 wt %, though anyfunctional concentration can be present at any effective ratio, i.e.lidocaine base to tetracaine base ratio. Typically, the lidocaine totetracaine base weight ratio can be from 2:1 to 1:2, and is often about1:1, though ratios outside of this range are often effective as well.

As set forth herein, the formulations of the present disclosure can haveinitial viscosities of about 40,000 centipoise to about 800,000centipoise. In one embodiment, the formulation can have a viscosity ofabout 70,000 centipoise to about 500,000 centipoise. These viscositiesallow for the formulations to be readily spread onto skin surfaceswithout running off. Further, it has been discovered that theformulations of the present disclosure have the unique ability tomaintain their viscosities in these ranges after multiple freeze/thawcycles. This ability provides a significant advantage over previousformulations. Formulations containing both PVA and water frequentlyexperience dramatic increases in viscosity after freeze/thaw cycles.Without being limited by theory, it is believed that the increase inviscosity in these PVA and water containing formulations is due to thetendency of the PVA to cross-link as a result of these cycles. Thisincrease in viscosity is particularly problematic for consumers andpractitioners who store the formulations in refrigerators to comply withthe storage recommendations for users. As the viscosity of theformulations increases, the formulations become increasingly difficultto expel or remove from their storage containers and to apply and spreadonto the skin surface, resulting in unusable and wasted formulations.Because refrigerators in the physicians' offices often reach freezingtemperatures (below 0° C.), it is desirable that the formulation canexperience freeze/thaw cycles without overly significant increases inviscosity.

Accordingly, in one embodiment of the present disclosure, theformulations have an initial viscosity from about 50,000 centipoise toabout 800,000 centipoise, and can have an increase in viscosity after atleast 3 freeze/thaw cycles of less than eight (8) times the initialviscosity with a maximum viscosity less than 1,500,000 centipoise. Inone embodiment, the increase in viscosity can be less than (5) times theinitial viscosity. In another embodiment, the formulations can have aninitial viscosity from about 70,000 centipoise to about 500,000centipoise, and can have an increase in viscosity after at least 3freeze/thaw cycles of less than five (5) times the initial viscositywith a maximum viscosity of 1,500,000 centipoise. In another embodiment,the formulations can have an initial viscosity from about 70,000centipoise to about 500,000 centipoise, and can have an increase inviscosity after at least 3 freeze/thaw cycles of less than three (3)times the initial viscosity with a maximum viscosity of 1,500,000centipoise. In a further embodiment, the formulations of the presentdisclosure can have an initial viscosity from about 70,000 centipoise toabout 500,000 centipoise, and can have an increase in viscosity after atleast 4 freeze/thaw cycles of less than three (3) times the initialviscosity with a maximum viscosity of 1,500,000 centipoise. In stillanother embodiment, the viscosity of the formulation after 3 freeze/thawcycles does not exceed 1,000,000 centipoise. In yet another embodiment,the viscosity of the formulation after 3 freeze/thaw cycles does notexceed 800,000 centipoise. In yet a further embodiment, the viscosity ofthe formulation after 3 freeze/thaw cycles does not exceed 500,000centipoise. Unless otherwise specified, all viscosity values in thecurrent disclosure are generated by the viscosity measurementmethodology set forth in Example 1.

It is noted that the reason it is desirable to not exceed 1,500,000centipoise (and more desirably less than 1,000,000 centipoise or evenless) after going through various freeze/thaw cycles is related to thecomposition becoming difficult to remove from a squeeze tube and applyto a skin surface after it gets much above this level of viscosity. Whenpractitioners refrigerate this material, if the composition becomesinadvertently frozen, if the viscosity is increased too much due tocrosslinking of the polyvinyl alcohol, the composition can becomevirtually unusable. Thus, acceptable freeze/thaw performance asdescribed herein represents a significant advancement in the art as itrelates to the specific types of compositions described herein.

Another unique parameter of the formulations of the present disclosureis the weight ratio of water to PVA in the formulation (water/PVAratio). It has been discovered that formulations having water to PVAratios above 2.4 have significantly better freeze-thaw performance thanthose with water/PVA ratio below that threshold. Accordingly, in oneembodiment, the formulations of the present disclosure have a water toPVA ratio (W/W) of at least 2.4. In another embodiment, the formulationshave a water to PVA ratio (W/W) of at least 2.5. In yet a furtherembodiment, the formulation can have a water to PVA ratio (W/W) of atleast 2.8.

The polyvinyl alcohol present in the formulations of the presentdisclosure facilitates the transition of the formulations from aninitial semi-solid initial state to a solidified state. Accordingly, itis desirable for the formulations to contain concentrations of PVAsufficient to facilitate this conversion. Formulations with excessivePVA concentrations can have high viscosities and be too difficult toapply or spread onto a skin surface. Similarly, formulations withinsufficient PVA concentrations can produce undesirably long dryingtimes and poor cohesion of the solidified formulation layer.Accordingly, in one aspect of the present disclosure, the formulationcan include 6 wt % to 25 wt % of polyvinyl alcohol. In another aspect ofthe disclosure, the formulation can include 10 wt % to 18 wt %.

The molecular mass of polyvinyl alcohol in the formulation is alsonotable in the context of the present disclosure. Used within theconcentration ranges described herein, the polyvinyl alcohol's averagemolecular mass can be in the range of 20,000 to 100,000 Daltons. Moretypically, the average molecular mass can be in the range of 30,000 to80,000 Daltons. When lower molecular mass PVA is used in theformulations of the current disclosure, the viscosity of theformulations can be too low for spreading on the skin and the cohesioncan be too weak to provide appropriate adherence to the skin. When PVAwith meaningfully higher molecular mass is used in the formulations ofthe present disclosure, the viscosity of the formulations can be toohigh and the manufacturing of the formulations in large scale can bedifficult (higher molecular mass PVAs are more difficult to dissolve).The average molecular mass of PVA used in the formulations of theexamples herein is typically in the range of 40,000 to 70,000 Daltons.

The solid-forming local anesthetic formulations of the presentdisclosure are in an initial semi-solid state before they are applied toa skin surface. After application, the formulations form a soft coherentsolid layer after the evaporation of sufficient amount of water. Thus,the formulation starts as a semi-solid. After being applied as a thinlayer (0.3-1.0 mm or more), the surface dries to the touch in about 5-30minutes and later the entire layer solidifies into a coherent softsolid. The solid-forming local anesthetic formulation can deliver thelocal anesthetics to the skin and underlying tissues from the moment itis applied on the skin surface until substantially all the water isevaporated from the formulation. Accordingly, the delivery of the localanesthetic agents continues after the formulation transforms into alayer of soft solid, because typically there is still significant amountof water in the formulation layer even after the formulation solidifies.After evaporation of substantially all of the water, delivery of thelocal anesthetics typically stops or slows significantly, although thetherapeutic effect may still be present long after the drug delivery hasstopped due to the storage of the local anesthetic agents in the skin,as well as by the mechanical protection provided by the coherent solidremaining on the skin surface. In one embodiment, the formulation caninclude 30 wt % to 55 wt % water. In another embodiment, formulation caninclude 35 wt % to 50 wt % water.

The formulations of the present disclosure are, by nature, oil-in-wateremulsions and may comprise two or more oil phases. For example, in oneembodiment, the formulations of the present disclosure can contain twooil phases: a mixture of lidocaine and tetracaine, e.g. eutectic mixtureof lidocaine and tetracaine, and petrolatum. The use of an emulsifyingagent or combination of emulsifying agents that can properly emulsifyall the oil phases can be significant. Hydrophile-lipophile balancenumber (HLB number) is a notable parameter that can be used incharacterizing emulsifying agents.

It has been discovered that emulsifying agents having HLB values of 6.7or greater do not properly emulsify certain formulations of the presentdisclosure, unless the water to polyvinyl alcohol ratio is increased. Insome embodiments, it has been discovered that in certain formulations ofthe current disclosure, Span 40 (Sorbitan monopalmitate, HLB 6.7) doesnot adequately emulsify the petrolatum for long periods of time, e.g.,separation occurs. That being said, it has been discovered thatemulsifiers having HLB values less than 6.7 (which excludes Span 40),and in particular, those with HLB values of less than 5, such as Span60, (Sorbitan monostearate, HLB 4.7), as well as some other emulsifyingagents with HLB numbers lower than 6.7, can properly emulsify both theeutectic mixture and petrolatum. Non-limiting examples of such effectiveemulsifying agents can include Glyceryl monostearate (HLB number 3.8),Sorbitan sesquioleate (HLB number 3.7), Span 65 (Sorbitan tristearate,HLB number 2.1), and Span 80 (Sorbitan monooleate, HLB number 4.3).

The formulations of the present disclosure are for pain control and canbe used to treat a variety of pains and their sources. In oneembodiment, the formulation can be used to treat neuropathic pain.Typically, the formulations of the present disclosure can provide relieffrom pain, e.g. neuropathic pain and post herpetic neuralgia, withinabout 60 minutes, about 45 minutes, or even in as short of a time aswithin about 30 minutes after application to a skin surface proximatethe pain. In order for the solid-forming local anesthetic formulation toprovide significant relief of the pain, it is generally desirable thatthe formulation remain on the skin surface of the subject for a periodof at least about 20 minutes. When the pain being treated is neuropathicpain, the source or underlying cause of the neuropathic pain beingtreated can vary. Non-limiting examples of causes of neuropathic paininclude diabetic neuropathies and pain associated withpostsurgical/post-traumatic conditions. Once applied, the solid-forminglocal anesthetic formulations of the present disclosure can be left onthe skin surface, either as the semi-solid or as the soft coherentsolid, for extended periods of time. After sufficient water evaporation,the semi-solid will form a soft coherent solid that can be removed fromthe skin as a solid, e.g., unlike in the initial state that has more ofa liquid or pasty consistency that can be removed by simple wiping, thesoft coherent solid can be removed as a solid piece or just a few solidpieces once transformed from semi-solid to solid.

EXAMPLES

The following examples illustrate the embodiments of the disclosure thatare presently best known. However, it is to be understood that thefollowing are only exemplary or illustrative of the application of theprinciples of the present disclosure. Numerous modifications andalternative compositions, methods, and systems may be devised by thoseskilled in the art without departing from the spirit and scope of thepresent disclosure. The appended claims are intended to cover suchmodifications and arrangements. Thus, while the present disclosure hasbeen described above with particularity, the following examples providefurther detail in connection with what are presently deemed to be themost practical embodiments of the disclosure.

Example 1—Viscosity Testing of the Formulations

The following outlines the testing procedures for measuring theviscosity of formulations of the present disclosure.

1. The samples to be tested are removed from the refrigerator and allowthem to equilibrate to room temperature (about 25° C.) for at least 1hour before handling.

2. Using a balance, place the empty small sample adapter (13R) on thebalance, and press the tare button. Once the adapter has been tared,fill it with sample material to approximately ⅓ of the total weight(about 7 grams). Tap the adapter on a hard surface for several secondsto remove any entrapped air that might be present in the bottom.Continue to fill the sample adapter ⅓ at a time with additional samplematerial while tapping to remove entrapped air until the sample weightis 20 to 21 grams (maximum).

3. Using a balance centrifuge, spin the sample in the adapter forapproximately 30 seconds at a high speed (approximately 4000 rpm) inorder to remove any additional air bubbles within the sample.

4. After centrifuging, add additional sample material (about 1 gram) toobtain a final sample weight that is 21 to 22 grams. Record the sampleweight (in grams).

5. Set the temperature controller on the viscometer to 23±2° C.Equilibrate the sample in the small sample adapter. Using a thermometer,insert the probe no more than 1 cm into the center of the sample, awayfrom the adapter walls.

6. The sample is now ready to be tested on the viscometer. Insert thesample adapter into the sample adapter holder, align the groove, andlock into place. Remove the back holder supporting the sample adapter byunscrewing the nut located behind the spindle coupling nut module. Alignthe spindle coupling link with the viscometer coupling nut, and rotatethe spindle clockwise. Replace the back holder, submerging the spindlein the middle of the sample holder at the same time. Avoid sampleperturbation as much as possible. Screw the nut maintaining the backadapter behind the spindle coupling nut module. The spindle should beimmersed in the sample up to the middle of the shaft indentation for theviscosity measurement. Failure to immerse the spindle up to the middleof the shaft indentation could result in a faulty viscosity reading.

7. Once the spindle is firmly in place, press the “SET SPEED” key once,and use the t or j arrows to set the spindle speed to 4.0 rpm. Press the“SET SPEED” key again. Once the proper speed (4.0 rpm) and spindle (7)are shown in the display, set the timer to countdown from 2 minutes.

8. Simultaneously start the timer and press the “MOTOR ON/OFF” key tobegin the viscosity measurement. Allow the reading to equilibrate for 2minutes before recording the viscosity reading and % torque value.

9. If the reading is out of the viscometer's range (% torquereading>100.0%), the cp and torque reading will display EEEE. At thispoint, turn off the motor, change the speed to the next lowest setting,and re-start the timer for 2 minutes. Turn the motor and timer onsimultaneously, and allow the reading to equilibrate for 2 minutesbefore recording the torque and viscosity values. If the torque andviscosity are still out-of-range (EEEE) continue to incrementally reducethe speed, and re-run the sample until % T and viscosity values are inrange.

10. After an equilibration time of 2 minutes has elapsed, record the %torque and viscosity values. Press the motor key off. At this point,unlock and carefully remove the sample adapter from the sample adapterholder. Remove the spindle from the viscometer by holding the viscometercoupling nut and rotating the spindle counter clockwise.

11. Remove the excess sample material from the spindle. The remainingsample in the sample adapter can be placed in the waste container.

Example 2

The viscosity of the formulation primarily impacts the difficulty ofsqueezing the product out of the tube and spreading the product on theskin. Lower viscosities are easier for both expulsion out of theircontainers and application to the skin, however formulations with overlylow viscosities may drip excessively out of the tube or run afterapplication to the skin.

Several formulations were produced with varying viscosities and havedemonstrated various viscosity ranges. The following formulations wereproduced and evaluated for wear properties. Formulation 1 with aviscosity of ˜28 k centipoise was easy to apply and spread, but wassomewhat runny. Formulations 2 and 3 showed slightly higher viscositiesalong with decreased tendency to run. Formulations 4 and 5 had yethigher viscosities, but were still easy to squeeze from the tube andvery easily spread in a flat layer. These higher viscosity formulationsshowed lower tendency to run. Formulation 6 with a viscosity of ˜828 kwas noticeably thicker and needed more effort to dispense and spread,but was still suitable for use for some applications, but would be lessdesirable for very sensitive skin surfaces, such as skin surfacessuffering from allodynia.

Formulation 1 2 3 3A 3B 4 5 6 Viscosity (cP) 28,460 47,800 67,800 79,500122,500 370,500 454,500 828,500 Ingredients Lidocaine (base)  7.00% 7.00%  7.00%  7.00%  7.00%  7.00%  7.00%  7.00% Tetracaine (base) 7.00%  7.00%  7.00%  7.00%  7.00%  7.00%  7.00%  7.00% Purified Water54.27% 37.94% 51.87% 39.94% 35.94% 35.94% 25.94% 25.94% DiCalcium —24.00% — 18.00% 27.00% 27.00% 36.00% 36.00% Phosphate Polyvinyl Alcohol21.60% 12.00% 24.00% 14.00% 14.00% 14.00% 12.00% 12.00% White Petrolatum 8.00% 10.00%  8.00% 10.00%  5.00%  5.00% 10.00% 10.00% Span 40  2.00% 2.00%  2.00% — —  4.00%  2.00%  2.00% (Sorbitan Monopalmitate) Span 60— — —  4.00%  4.00% (Sorbitan Monostearate) Methylparaben  0.10%  0.05% 0.10%  0.05%  0.05%  0.05%  0.05%  0.05% Propylparaben  0.03%  0.01% 0.03%  0.01%  0.01%  0.01%  0.01%  0.01% Total   100%   100%   100%  100%   100%   100%   100%   100%

Example 3

The total water content of the formulation is significant from thestandpoint of chemical stability and drying time. It has been shown thatin aqueous solutions, tetracaine hydrolyzes to 4-butylaminobenzoic acid(4-BABA) and 2-dimethylaminoethanol (DMAE). Thus, degradation productsin the formulation should be minimized in order to ensure optimalpotency and purity of the formulation. Studies of various formulations(see table below) have shown that the levels of 4-BABA in theformulation correlate to the total water content in the formulation. Inthe sense that it is desirable to maintain levels of 4-BABA below 3%after 24 months of storage at 5° C. (shelf-life), for example, it wouldbe desirable to ensure total water content remains below ˜50%.

Formulation 7 8 9 10 11 Water Content 29.54%  31.94%  42.82%  48.88% 51.87%  4-BABA level after 12 0.75% 0.82% 1.09% 1.42% 1.50% monthsstorage at 5° C. Projected 4-BABA level 1.50% 1.64% 2.18% 2.84% 3.00%after 24 months storage at 5° C. Ingredients Lidocaine (base) 7.00%7.00% 7.00% 7.00% 7.00% Tetracaine (base) 7.00% 7.00% 7.00% 7.00% 7.00%Purified Water 29.54%  31.94%  42.82%  48.88%  51.87%  DiCalciumPhosphate 32.40%  30.00%  — — — Polyvinyl Alcohol 12.00%  12.00% 19.77%  27.00%  24.00%  White Petrolatum 10.00%  10.00%  — 8.00% 8.00%Span 40 (Sorbitan 2.00% 2.00% 3.30% 2.00% 2.00% Monopalmitate)Methylparaben 0.05% 0.05% 0.09% 0.10% 0.10% Propylparaben 0.01% 0.01%0.02% 0.02% 0.03% Corn Starch — — 20.00%  — — Total  100%  100%  100% 100%  100%

Since the evaporation of water causes the formulation to form asolidified layer, it is expected that total water content will directlyimpact drying time. Several formulations were studied to assess theimpact of water content on drying time, and the results provided belowindicate that a formulation with ˜30% water was completely dry to thetouch in approximately 10 minutes, whereas formulations with 40% and 54%water needed approximately 30 and 60 minutes, respectively, to be dry tothe touch. Dry to the touch means the surface of the formulation layeris solidified enough so that a light touch by a finger does not removeany formulation from the layer.

Formulation 12 13 14 Water Content 31.94%  39.94%  54.27%  Drying TimeLess than 10 Between 10-30 Between 30-60 minutes minutes minutesIngredients Lidocaine (base) 7.00% 7.00% 7.00% Tetracaine (base) 7.00%7.00% 7.00% Purified Water 31.94%  39.94%  54.27%  DiCalcium 30.00% 18.00%  — Phosphate Polyvinyl Alcohol 12.00%  14.00%  21.60%  WhitePetrolatum 10.00%  10.00%  8.00% Span 40 (Sorbitan 2.00% — 2.00%Monopalmitate) Span 60 (Sorbitan — 4.00% — Monostearate) Methylparaben0.05% 0.05% 0.10% Propylparaben 0.01% 0.01% 0.03% Total  100%  100% 100%

Example 4

Since the formulations herein may be stored in refrigerated conditions,the impact of freezing or cycling temperatures (freeze-thaw) on theformulations is considered. Freeze-thaw cycles may cause the PVAmolecules in the formulations to crosslink, resulting in a dramaticincrease in viscosity which may make the formulation difficult to spreadon skin or even remove from an application tube. A series of cycling(freeze-thaw) studies was performed on several formulations in order toassess the impact of exposure to multiple “freeze-thaw” cycles. Onefreeze-thaw cycle is defined as exposure to freezing conditions (e.g.,−18° C. to 22° C.) for 48 hours followed by exposure to room temperaturethawing conditions (e.g., about 25° C.) for 48 hours. A more robustformulation will show less increase in viscosity after exposure tomultiple freeze-thaw cycles. It is noted that exceeding the 48 hour timeperiods for freezing and thawing for a short period of time willtypically not impact the test results. Several formulations have beendeveloped and subjected to freeze-thaw cycles. Viscosity at baseline andafter each freeze-thaw cycle was measured using the method outlined inExample 1.

The data gathered on the formulations below indicate that the water toPVA ratio has an impact on the resistance to freeze/thaw exposures.Formulations having a water:PVA ratio greater than 2.5 demonstrated lesspronounced viscosity increases after exposure to multiple freeze/thawcycles, as shown in the table below.

Formulation 15 16 17 18 19 Water/PVA ratio 2.16 2.46 2.57 2.85 3.16Ingredients Lidocaine (base) 7.00% 7.00% 7.00% 7.00% 7.00% Tetracaine(base) 7.00% 7.00% 7.00% 7.00% 7.00% Purified Water 25.94%  29.54% 35.94%  39.94%  37.94%  DiCalcium Phosphate 36.00%  32.40%  27.00% 18.00%  24.00%  Polyvinyl Alcohol 12.00%  12.00%  14.00%  14.00% 12.00%  White Petrolatum 10.00%  10.00%  5.00%  10.00%  10.00%  Span 40(Sorbitan 2.00% 2.00% — — 2.00% Monopalmitate) Span 60 Sorbitan — —4.00% 4.00% — Monostearate) Methylparaben 0.05% 0.05% 0.05% 0.05% 0.05%Propylparaben 0.01% 0.01% 0.01% 0.01% 0.01% Total  100%  100%  100% 100%  100% Initial Viscosity 454,500 146,000 122,500 79,500 47,800Freeze/Thaw Viscosity Results 1 cycle 7,200,000 436,500 170,000 94,50029,440 2 cycles >8,000,000 427,000 226,500 114,000 29,160 3cycles >8,000,000 1,150,000 210,000 146,000 33,080 4 cycles >8,000,0002,385,000 227,500 87,000 46,400 5 cycles >8,000,000 3,310,000 333,000137,500 38,000 Freeze/Thaw Viscosity Increase Multiple 1 cycle 16 3 1 11 2 cycles >18 3 2 1 1 3 cycles >18 8 2 2 1 4 cycles >18 16 2 1 1 5cycles >18 23 3 2 1

Example 5

Two solid-forming local anesthetic formulations were made and theircompositions are listed in the following table. The formulations areidentical except Formulation 20 used Span 40 (Sobitan Monopalmitate) asemulsifying agent and Formulation 21 used Span 60 (SorbitanMonostearate). After about three months, Formulation 20 showedsignificantly more phase separation that Formulation 21.

Formulation 20 21 Ingredients Lidocaine 7.00% 7.00% Tetracaine 7.00%7.00% Purified Water 35.94%  35.94%  DiCalcium Phosphate 27.00%  27.00% Polyvinyl Alcohol 14.00%  14.00%  White Petrolatum 5.00% 5.00% Span 40(Sobitan 4.00% — Monopalmitate) Span 60 (Sorbitan — 4.00% Monostearate)Methylparaben 0.05% 0.05% Propylparaben 0.01% 0.01% Total  100%  100%Initial Viscosity 132,000 122,500 Water/PVA ratio 2.57 2.57

Example 6

Three solid-forming local anesthetic formulations were made and theircompositions are listed in the following table. The formulations wereidentical except that the emulsifying agents were different: Span 65(Sorbitan tristearate, HLB number 2.1) was used in formulation 31, Span80 (Sorbitan monooleate, HLB number 4.3) was used in Formulation 32, andSpan 85 (Sorbitan trioleate, HLB number 1.8) was used in Formulation 33.After about three weeks, none of the formulations showed detectablephase separation.

Formulation Number Ingredients 22 23 24 Lidocaine 7.00% 7.00% 7.00%Tetracaine 7.00% 7.00% 7.00% Purified Water 35.94% 35.94% 35.94%DiCalcium Phosphate 27.00% 27.00% 27.00% Polyvinyl Alcohol 14.00% 14.00%14.00% White Petrolatum 5.00% 5.00% 5.00% Sorbitan tristearate (Span 65)4.00% Sorbitan monooleate, (Span 80) 4.00% Sorbitan trioleate (Span 85)4.00% Methylparaben 0.05% 0.05% 0.05% Propylparaben 0.01% 0.01% 0.01%Water/PVA ratio 2.57 2.57 2.57

While the invention has been described with reference to certainembodiments, those skilled in the art will appreciate that variousmodifications, changes, omissions, and substitutions can be made withoutdeparting from the spirit of the disclosure. It is therefore intendedthat the invention be limited only by the scope of the appended claims.

What is claimed is:
 1. A solid forming local anesthetic formulation,comprising: lidocaine, tetracaine, from about 10 wt % to about 18 wt %polyvinyl alcohol, from about 30 wt % to about 50 wt % water, and anemulsifying agent, wherein the water to polyvinyl alcohol weight ratio(w/w) is greater than 2.4.
 2. The formulation of claim 1, wherein thelidocaine and tetracaine are collectively present in the formulationfrom about 8 wt % to about 20 wt %.
 3. The formulation of claim 2,wherein the lidocaine is present in the formulation from about 4 wt % toabout 10 wt % and the tetracaine is present in the formulation fromabout 4 wt % to about 10 wt %.
 4. The formulation of claim 1, whereinthe lidocaine and tetracaine are each in their base form.
 5. Theformulation of claim 4, wherein the lidocaine and tetracaine are in theform of a eutectic mixture.
 6. The formulation of claim 1, wherein thepolyvinyl alcohol has an average mass from about 30,000 Daltons to about80,000 Daltons.
 7. The formulation of claim 1, wherein the emulsifyingagent comprises sorbitan monopalminate or sorbitan monostearate.
 8. Theformulation of claim 1, wherein the emulsifying agent is sorbitanmonostearate.
 9. The formulation of claim 1, further comprisingpetrolatum.
 10. The formulation of claim 1, wherein the water topolyvinyl alcohol ratio is greater than 2.5.
 11. The formulation ofclaim 1, wherein the lidocaine and tetracaine is present as a eutecticmixture at a 2:1 to 1:2 weight ratio.
 12. The formulation of claim 1,wherein the lidocaine and tetracaine is present as a eutectic mixture atabout a 1:1 weight ratio.
 13. The formulation of claim 1, wherein theformulation comprises 7 wt % lidocaine and 7 wt % tetracaine.
 14. Theformulation of claim 1, wherein the formulation is for local anesthesia.15. A solid forming local anesthetic formulation, comprising: a eutecticmixture of lidocaine and tetracaine, from about 10 wt % to about 18 wt %polyvinyl alcohol, from about 30 wt % to about 50 wt % water,petrolatum, and sorbitan monostearate, wherein the water to polyvinylalcohol weight ratio (w/w) is greater than 2.4.
 16. The formulation ofclaim 15, comprising: 8 wt % to 20 wt % of the eutectic mixture oflidocaine and tetracaine, 2 wt % to 13 wt % of the petrolatum, and 2 wt% to 6 wt % of the sorbitan monostearate.
 17. The formulation of claim15, comprising: 7 wt % of the lidocaine, 7 wt % of the tetracaine, 35.94wt % of the water, 14 wt % of the polyvinyl alcohol, and 4 wt % of thesorbitan monostearate.
 18. The formulation of claim 15, wherein thewater to polyvinyl alcohol ratio is greater than 2.5.
 19. Theformulation of claim 15, wherein the polyvinyl alcohol has an averagemass from about 30,000 Daltons to about 80,000 Daltons.
 20. Theformulation of claim 15, wherein the formulation is for localanesthesia.